Hot flashes (also called vasomotor flashes) are the most common symptoms experienced by women who are perimenopausal or postmenopausal. Hot flashes are also a common and potentially chronic problem in men with prostate cancer who undergo androgen deprivation therapy (ADT). This is a major quality of life issue for a significant proportion of men receiving ADT. One report shows that the natural history of hot flashes in men, including variation in severity and frequency, has not been widely studied. Almost 70 percent of men who undergo surgical orchiectomy report hot flushes. About 70 to 80 percent of men on long-term androgen suppression have hot flushes, and 30 to 40 percent of these patients report that symptoms are a major source of discomfort (Steams, V., Ullmer, L., Lopez, J. F., Smith, Y., Isaacs, C., and Hayes, D. (2002) Hot flushes. Lancet 360: 1851-1861.)
Hot flashes are a sudden sensation of warmth, which are usually accompanied by skin reddening, perspiration, palpitation, anxiety, irritability, and even panic, and night sweats. A chill may follow a hot flash because of a subsequent drop in core temperature. Hot flashes vary: they can be several times a week or once per hour, they can be characterized by mild warmth to profuse sweating, and they can last from several seconds to 60 minutes. Such symptoms can disrupt sleep and work and interfere with quality of life.
Almost 60-70% of postmenopausal women have hot flashes, and approximately 10-20% of all postmenopausal women will report intolerable symptoms, including hot flashes. Some women may suffer from these symptoms for up to 15 years (Kronenberg F. “Hot flashes: epidemiology and physiology,” Ann N Y Acad Sci, 592:52-86(1990)). Thus, the identification and proper management of menopausal symptoms are crucial to maintaining a woman's quality of life.
Typical hot flashes occur with sudden onsets of sensation of warmth in the chest, which then spreads upward to involve the neck and face. Hot flashes can last from a few seconds to several minutes. However, the severity of the sensations vary greatly both from time to time in the same woman and from woman to woman. Hot flashes may be accompanied by dizziness, nausea, headaches, palpitations, profuse sweating and night sweats. How often a woman experiences hot flashes also varies, ranging from many times a day to once a week or less. Such symptoms can disrupt sleep and work and interfere with quality of life. In some women, hot flashes are provoked by several factors such as hot weather, stress, eating, or drinking alcohol.
Although the pathophysiology of hot flashes is not completely understood, it has been postulated that hot flashes result from a transient lowering of the hypothalamic temperature regulatory set point (Steams et al., “Hot flushes,” Lancet, 360:1851-1861 (2002)). Because of the temporal relation between changes in sexual hormone concentrations and the onset of hot flashes, it is believed that such symptoms result from declining estrogen levels or increased gonadotropin concentrations. Thus, hot flashes occur commonly in menopausal women, but also in women taking anti-estrogen drugs, such as tamoxifen. Men on androgen deprivation treatment may also experience such symptoms.
Although estrogen replacement therapy can effectively minimize or prevent hot flashes in women, many women are concerned about potential risks of hormone replacement therapy. This is especially true for women who suffer from breast cancer or have a family history of breast cancer, and/or a history of clotting disorder (Col et al., “Patient-specific decisions about hormone replacement therapy in postmenopausal women,” JAMA, 277; 1140-1147 (1997); Gail et al., “The menopause,” Lancet, 353:571-580 (1999)).
Various non-hormonal agents have been tested as well, such as clonidine. Clonidine is a centrally-acting □2 adrenergic receptor agonist. It selectively stimulates receptors in the brain that monitor catecholamine levels in the blood. These receptors close a negative feedback loop that begins with descending sympathetic nerves from the brain that control the production of catecholamines (e.g., epinephrine, also known as adrenaline, and norepinephrine) in the adrenal medulla. By tricking the brain into believing that catecholamine levels are higher than they really are, clonidine causes the brain to reduce its signals to the adrenal medulla, leading to lower catecholamine production. The result is a lowered heart rate and blood pressure. In randomized clinical trials, clonidine was shown to be moderately more efficacious than placebo (Goldberg et al., “Transdermal clonidine for ameliorating tamoxifen-induced hot flashes,” J Clin Oncol. 12:155-158 (1994); Pandya et al., “Oral clonidine in postmenopausal patients with breast cancer experiencing tamoxifen-induced hot flashes: a University of Rochester Cancer Center Community Clinical Oncology Program study,” Ann Intern Med. 132:788-793 (2000)), but adverse effects are common, including dry mouth, dizziness, and blurred vision.
Recent randomized clinical trials also confirmed that some selective serotonin-reuptake inhibitors (SSRI), such as venlafaxine and paroxetine, are more effective than placebo in minimizing the occurrence and severity of hot flashes (Loprinzi et al., “Venlafaxine in management of hot flashes in survivors of breast cancer: a randomised controlled trial,” Lancet 356:2059-2063 (2000); Stearns et al., “Paroxetine controlled release in the treatment of menopausal hot flashes: A randomized controlled trial,” JAMA 289:2827-2834 (2003)). However, adverse effects with SSRIs are moderate, including headache, agitation, tremor, sedation, and sexual dysfunction.
There are also a number of treatments for hot flashes that appeared to have similar effects in men and women. Decreases of hot flash frequencies in women treated with clonidine are approximately 10-15 percent greater than that seen with placebo. In a double blind, cross over study of clonidine to reduce self-reported hot flash frequency in men, a similar effect was seen, but the difference from placebo effect was not statistically significant. Research has found virtually identical results for men and women receiving megestrol acetate for hot flashes, with approximately an 80 percent reduction in self-reported hot flash frequency compared to a 20 percent reduction with placebo.
Many women seek complementary and alternative medicine (CAM) methods to ease their menopausal symptoms. Compounds used as complementary and alternative medicine can be selected from the group consisting of Soy Vitamin E, Red clover (Trifolium pratense), dong quai, evening primrose oil, black cohosh (Cimicifuga racemosa) J Support Oncol 2003; 1:11-21.
Over the last few years, anecdotal reports suggested that antidepressants from the SSRI/SNRI groups might reduce symptoms of hot flashes. These observations led to initial pilot studies and then to randomized placebo controlled clinical trials. In pilot studies, the SNRI venlafaxine (Effexor) and the SSRI paroxetine (Paxil) were associated with hot-flash score reductions on the order of 55%-75%. Other pilot evaluations have suggested that citalopram (Celexa) and mirtazapine (Remeron) also alleviate hot flashes to a similar degree. The first reported randomized clinical trial of one of these newer antidepressants compared three doses of venlafaxine (37.5, 75, and 150 mg/day) to placebo. While low-dose venlafaxine was only mildly more effective than placebo (37% vs 27% reduction in hot-flash scores, respectively), both the moderate and high doses were associated with a statistically significant 61% reduction in hot flash scores. Fluoxetine (Prozac) 20 mg/day was associated with a 50% reduction in hot-flash scores compared to a 36% reduction with placebo (P=0.02).
More recently, anecdotal observations suggesting efficacy led to trials to assess the value of another compound, gabapentin (Neurontin). Gabapentin is a γ-aminobutyric acid (GABA) analog that has been most often prescribed for the treatment of seizures and naturopathic pain. It is also effective in other syndromes, such as panic disorder, social phobia, migraine headache, and essential tremor. Based on anecdotal observations, pilot and randomized trials of gabapentin for the treatment of hot flashes were launched. Results of the pilot trials suggested that gabapentin reduces the incidence of hot flashes by 42%-70%. Benefit was demonstrated regardless of the concurrent use of a stable dose of an SSRI/SNRI agent.
Given the risks of estrogen replacement therapy and marginal benefits of current non-hormonal treatments, there is a continued need for alternative methods or drugs for treating or preventing symptoms associated with menopause, surgery and/or androgen deprivation therapy, including hot flashes.